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TitleStructural basis of α-scorpion toxin action on Na channels.
Journal, issue, pagesScience, Vol. 363, Issue 6433, Year 2019
Publish dateMar 22, 2019
AuthorsThomas Clairfeuille / Alexander Cloake / Daniel T Infield / José P Llongueras / Christopher P Arthur / Zhong Rong Li / Yuwen Jian / Marie-France Martin-Eauclaire / Pierre E Bougis / Claudio Ciferri / Christopher A Ahern / Frank Bosmans / David H Hackos / Alexis Rohou / Jian Payandeh /
PubMed AbstractFast inactivation of voltage-gated sodium (Na) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na ...Fast inactivation of voltage-gated sodium (Na) channels is essential for electrical signaling, but its mechanism remains poorly understood. Here we determined the structures of a eukaryotic Na channel alone and in complex with a lethal α-scorpion toxin, AaH2, by electron microscopy, both at 3.5-angstrom resolution. AaH2 wedges into voltage-sensing domain IV (VSD4) to impede fast activation by trapping a deactivated state in which gating charge interactions bridge to the acidic intracellular carboxyl-terminal domain. In the absence of AaH2, the S4 helix of VSD4 undergoes a ~13-angstrom translation to unlatch the intracellular fast-inactivation gating machinery. Highlighting the polypharmacology of α-scorpion toxins, AaH2 also targets an unanticipated receptor site on VSD1 and a pore glycan adjacent to VSD4. Overall, this work provides key insights into fast inactivation, electromechanical coupling, and pathogenic mutations in Na channels.
External linksScience / PubMed:30733386
MethodsEM (single particle)
Resolution3.4 - 3.5 Å
Structure data

0500

6nt3

EMDB-0500, PDB-6nt3:
Cryo-EM structure of a human-cockroach hybrid Nav channel.
Method: EM (single particle) / Resolution: 3.4 Å

0501

6nt4

EMDB-0501, PDB-6nt4:
Cryo-EM structure of a human-cockroach hybrid Nav channel bound to alpha-scorpion toxin AaH2.
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose / N-Acetylglucosamine

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-76F:
(7E,21R,24S)-27-amino-24-hydroxy-18,24-dioxo-19,23,25-trioxa-24lambda~5~-phosphaheptacos-7-en-21-yl (9Z,12E)-octadeca-9,12-dienoate / Discrete optimized protein energy

ChemComp-LHG:
1,2-DIPALMITOYL-PHOSPHATIDYL-GLYCEROLE / phospholipid*YM / Phosphatidylglycerol

ChemComp-AJP:
Digitonin / detergent*YM / Digitonin

Source
  • periplaneta americana (American cockroach)
  • Sahara scorpion (Sahara scorpion)
  • homo sapiens (human)
  • androctonus australis (Sahara scorpion)
KeywordsMEMBRANE PROTEIN / Sodium channel / scorpion toxin / electrical signaling / fast inactivation

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